Herpes simplex is a ubiquitous pathogen maintained in a latent stage in neurosurgery ganglia of the host, with episodic reactivation. Although certain events (emotional stress, ultraviolet light exposure, memstruation) precipitate reactivation, the basis for such recurrences is not known. The long-range goal of this proposal is to define the importance of fluctuations in immunosurveillance as a causal factor in reactivation of oral HSV-1 infection. In view of the morbidity attributable to recurrent HSV infection and its possible oncogenic potential, this is a health-related issue. Preliminary data indicate that recurrence of oral HSV is associated with transient activation of adherent suppressor cells and a qualitative change in natural killer cell activity (resistance to Gamma-irradiation). This proposal tests the hypothesis that stress, by increasing circulating mediators such as Beta-endorphins, activates adherent suppressor cells in subjects with frequent recurrence of HSV infection. The adherent suppressor cell interferes with two critical anti-viral effector medchanisms: a) IL-2 production essential for specific cytotoxic T-cell function, and b) NK-like cells which destroy HSV-infected targets. Reactivation is favored by the resultant lapse in immune surveillance. The study populations consist of groups of subjects with primary oral HSV-1 infection, frequent recurrences of oral HSV-1 infection, and asymptomatic seronegative and seropositive controls. HSV-1 infected and age- and sex-matched controls will be evaluated clinically, virologically and immunologically. These studies should identify changes in cellular immune and nonspecific effector mechanisms triggered by stress which precede and predispose to reactivation of oral HSV-1 infection. Specific Aims are: 1) To characterize the phenotype and mechanism of action of the suppressor adherent cell which inhibits blastogenic responses during recrudescence or oral HSV infection in subjects with frequent recurrences; 2) To evaluate regulation of production of two lymphokines critical to anti-viral effector function, interleukin-2 and Gamma-interferon, during recurrence of oral HSV infection, with particular attention to the role of suppressor adherent cells defined in S.A.1; 3) To examine modulation of natural killer-like activity for HSV-1 infected human fibroblasts during recrudescence of oral HSV-1 infection and its relationship to NK activity; 4) To evaluate the relationship between stress, Beta-endorphins, activation of suppressor cells and recurrence of oral HSV infection.